Method and apparatus for treatment of adipose tissue

ABSTRACT

The invention provides methods and apparatuses for the treatment of adipose tissue. The methods comprise application of ultrasound energy to a region of adipose tissue, and the apparatuses comprise at least one source of ultrasound energy configured to direct ultrasound energy through a skin surface into the subcutaneous adipose tissue. In one embodiment, a pressure gradient is created in the region generating relative movement between fat cell constituents having different densities. In another embodiment, a protrusion of skin and underlying adipose tissue containing is formed and ultrasound energy is radiated into the adipose tissue in the protrusion. In another embodiment, an RF electric field is generated inside a region of adipose tissue together with the ultrasound energy.

FIELD OF THE INVENTION

The invention relates to methods and apparatuses for the reduction ofadipose (fat) tissue.

LIST OF REFERENCES

The following references are brought to facilitate description of thebackground of the present invention, and should not be construed aslimiting the scope or patentabililty of the invention:

-   U.S. Pat. No. 5,143,063-   U.S. Pat. No. 5,158,070-   US Patent Applications Nos. 2005/0154431 and 2004/0106867-   U.S. Pat. No. 6,607,498-   U.S. Pat. No. 6,113,558-   U.S. Pat. No. 6,889,090-   U.S. Pat. No. 5,871,524-   U.S. Pat. No. 6,662,054-   S. Gabriel, R. W. Lau, and C. Gabriel, Phys. Med. Biol. 41 (1996),pp    2251-2269-   Luc Fournier and Be'la Joo's, Physical review 67, 051908 (2003)-   Alster T. S. and Tanzi, E. L., The Journal of Cosmetic and Laser    Therapy. 2005; 7: 81-85-   “Physical properties of tissue”, by Francis A. Duck, Academic Press    Ltd., 1990, p. 138, the density of adipose tissue is 916 Kg/m³-   “Physical properties of tissue”, by Francis A. Duck, Academic Press    Ltd., 1990, p. 85 Herve Isambert, Phys. Rev. Lett. 80, p 3404 (1998)-   K. Y. Saleh and N. B. Smith, Int. J. Hyperthermia Vol. 20, NO. 1    (February 2004), pp. 7-31.

BACKGROUND OF THE INVENTION

Reduction of subcutaneous fat layers, or adipose tissue, is an aesthetictreatment for which there is a growing demand. One method, liposuction,is a very aggressive invasive treatment requiring local or generalanesthesia, and the subsequent healing process is very long and painful.Methods for non-invasive local reduction of fat are based on thedelivery of electromagnetic or sound energy through the skin into thesubcutaneous adipose tissue. The main challenge with non-invasivetreatment of fat tissue is to transfer the energy through the outerlayers of the skin, and concentrating it to the required level in thefat tissue with minimal collateral damage to the skin layers and deeperbody tissues.

U.S. Pat. No. 5,143,063 describes a method for destruction of fat cells(adipocytes) in subcutaneous adipose tissue, in which radiant energy isfocused into these cells. The radiant energy may be electromagnetic inthe microwave range, or ultrasound. The major mechanism for celldestruction is the heat generated by the radiant energy. Only at thefocal volume is the energy density high enough for cell destruction,while outside the focal volume the energy density is lower than thedamage threshold. There is no specific selectivity for destruction offat cells, only a geometrical selectivity created by the focusing.

U.S. Pat. No. 5,158,070 discloses use of ultrasound pulses of shortduration that are powerful enough to tear soft tissue. Ultrasound pulseshaving a frequency between 3 MHz to 10 MHz and a pulse length of oneμsec to one msec are focused in the soft tissue to effect tearing anddestruction. Due to the application of short intense pulses, mechanical,and not thermal, effects are presumed to be responsible for the tissuedestruction. The following calculation provides an estimate for the peakpressure of the ultrasound wave required for this cell tearing. Assuminga plane ultrasound wave for which the cell size is much smaller then thewavelength, the local displacement U(x) is given by:

U(x)=U _(max) sin(ωt−kx)

where U_(max) is the maximum displacement given by:

$U_{\max} = \frac{V_{\max}}{\omega}$

V_(max) is the maximum velocity, ω=2πf, f is the frequency of theultrasound, and k is the wave vector. For a plane wave, ω=kc, where c isthe sound velocity at the tissue. Taking the derivative of U withrespect to x, the strains obtained:

$\frac{U}{x} = {{{- k}\frac{V_{\max}}{\omega}{\cos ( {{\omega \; t} - {kx}} )}} = {\frac{- V_{\max}}{c}{\cos ( {{\omega \; t} - {kx}} )}}}$

The maximal strain is V_(max)/c. The strength of a typical cell membranehas been investigated, and it was found that stretching a cell membraneby more then 2% causes it to tear, leading to cell necrosis, (LucFournier and Be'la Joo's, Physical review 67, 051908 (2003)). Thiscorresponds to a strain of 0.02. Since the sound velocity in a typicalsoft tissue is about 1500 m/sec, for rupturing a cell membrane, V_(max)has to be over 30 m/sec. For a plane wave, V=P/Z, where P is thepressure and Z is the acoustic impedance of the tissue, a typical valuefor Z is 1.5 MRayleigh, so that P has to be greater than 45 MPa. Thisnumber corresponds to a very intense ultrasound, which can be achievedwith a very high degree of focusing, and which is obtainable atfrequencies in the range of a few MHz. For example, US PatentApplication No. 2005/0154431, discloses adipose tissue destructiongenerated by HIFU (High Intensity Focused Ultrasound), with a typicalfrequency of 1-4 MHz and a pressure of about 30 MPa, close to thetheoretical estimate of 45 Mpa obtained above.

This method of cell rupturing is also not selective for adipose tissuecells (adipocytes) because the adipocyte membrane is not weaker thanthat of other cells. Also the shape and size of the cell did not enterin the above considerations. In this respect, cell destruction byrupturing the cell membrane is similar to cell destruction by heatingthe cells (hyperthermia). Neither method is selective for adipocytes,and any selectivity in the method relies on geometry i.e. very strongfocusing of the radiation in the adipose tissue. For both methods, ahigh degree of focusing yields a very small focal volume where celldestruction occurs. A typical effective focal width is a fewmillimeters. Therefore, the focal volume has to be moved over thetreated area. US Patent Applications Nos. 2005/0154431 and 2004/0106867disclose such a system.

Another physical effect of focused ultrasound that can cause cell lysis,is cavitations. Cavitations are small bubbles, starting from initialsmall gas nucleation centers, which are driven larger by the negativepressure phase of the ultrasound wave. The rate of generation and growthof cavitations is an increasing function of the amplitude of thepressure, therefore an increasing function of the ultrasound powerdensity. Under certain critical conditions, the bubbles collapseviolently, generating in their vicinity shock waves and fluid jets thatcan destroy cells. In liquid environments, especially in aqueoussolutions, there is evidence that collapse of cavitations causes cellgnecrosis and apoptosis. U.S. Pat. No. 6,607,498 discloses focusingultrasound energy on adipose tissue to cause cavitations and lysis ofadipose tissue. U.S. Pat. No. 6,113,558 discloses the application offocused pulsed ultrasound, which causes cavitations, for non-invasivetreatment of tissues. This last patent contains a list of possibleapplications, which include the induction of apoptosis and necrosis,clot lysis, and cancer treatment. This patent includes a study on thegeneration of cavitations and on the optimization of pulse width andpulse repetition rate for maximizing the cavitations. The cavitationthreshold for a non-degassed buffer solution and blood are in the rangeof 1000-1500 W/cm², while for degassed fluids the threshold rises to2000 W/cm². The ultrasound frequency in these experiments was 750 kHz.Cavitation damage is not cell selective, and can be induced on many celltypes. The cavitation threshold is quite high, and can be expected to bemuch higher inside adipose tissue, since most of the tissue volume isfat (lipid vacuoles). As with thermal treatment and mechanical rupturingof cells by ultrasound, also with cavitation, a high degree of focusingis required to ensure treatment of the selected tissue only (geometricalselectivity). There is another reason for the importance of focusing incavitation treatment: Cavitations absorb ultrasound very strongly.Therefore, if cavitations are created close to the applicator, that isbetween the focal region and the ultrasound radiating transducer (forexample at the skin), then most of the ultrasound energy will bedissipated there and will not reach the target tissue in the focalvolume. To prevent this from occurring, the focusing must be sufficientto assure an intensity above the minimum value for cavitation at thefocal volume, while the intensity at other tissues between thetransducer and focal volume must be below the threshold for cavitation.

Besides ultrasound and microwave radiation, application of RF (RadioFrequency) energy can affect both the skin and subcutaneous layers. U.S.Pat. No. 6,889,090 discloses the application of RF energy for skintreatment. U.S. Pat. No. 5,871,524, describes application of radiantenergy through the skin to an underlying subcutaneous layer or deepersoft tissue layers. The main energy source is RF. A bi-polar RFapplication, such as described in U.S. Pat. No. 6,889,090, is preferredover unipolar RF, since in unipolar RF currents flow throughuncontrolled channels at the body, and may cause unwanted damage.

RF energy is applied to the body through two conducting electrodesapplied to the skin between which an alternating voltage is driven. TheRF current flows according to Ohm's law through the conducting tissues,generating heat, which can affect the tissue. The conductivity of theskin layers is an order of magnitude larger than that of fat tissue.Typical skin conductivity is about 0.45/m and that of adipose tissue isabout 0.045/m at RF frequencies between 100 kHz and 10 MHz (S. Gabriel,R. W. Lau, and C. Gabriel, Phys. Med. Biol. 41 (1996), pp 2251-2269).Therefore most of the current flows through the skin layers, which isgood for skin treatments, for example, hair removal and skinrejuvenation. However, it is less efficient for treatment of the deeperadipose layers.

U.S. Pat. No. 6,662,054 discloses the application of negative pressure(vacuum) to a region of the skin, so that this region protrudes out ofthe surrounding skin, and applying RF energy to the protrusion viaelectrodes. Under negative pressure, the path between the RF electrodesis longer along the skin than through the subcutaneous layers.Therefore, more RF energy is delivered into subcutaneous layers thanthrough the skin. A commercial system based on U.S. Pat. No. 6,662,054has proved efficient for treatment of cellulites (TINA S. ALSTER &ELIZABETH L. TANZI, The Journal of Cosmetic and Laser Therapy. 2005; 7:81-85). Cellulite is clinically manifested by irregular skin contours ordimpling of the skin. It is caused by excess adipose tissue retentionwithin fibrous septae. The skin irregularity is proportional to thesubcutaneous fat projected into the upper dermis.

Most of the volume of an adipocyte is occupied by a fat fluid drop,known as a lipid vacuole. The typical diameter of the cell is 50-100 μmIt tends to 100 μm in adipose tissue of obese people. Between the lipidvacuole and cell membrane, is cytoplasm. Typically the width of thecytoplasm is only a few micrometers and it is not uniform around thelipid vacuole. It can be in the range from below 1 μm in one region ofthe cell and 3-5 μm in other regions.

The macroscopic physical properties of adipose tissue, mass density andsound velocity, are dominated by the material of the lipid vacuole,which occupies most of the tissue volume in mature fat cells which arethe cells to be treated in reduction of the fat layer. The physicalproperties of the lipid vacuole fluid are thus almost identical to thoseof fat tissue. The density of adipose tissue is about 10% lower thanthat of other body tissues. According to “Physical properties oftissue”, by Francis A. Duck, Academic Press Ltd., 1990, p. 138, thedensity of adipose tissue is 916 Kg/m³, while that of body fluids andsoft tissue are above 1000 Kg/m³ (i.e. above the density of water). Thedermis density is about 1100 Kg/m³, while that of muscles is 1040 Kg/m³.The cytoplasm and intercellular fluid are aqueous solutions so thattheir density is expected to be similar to that of other body fluids andsoft tissues, i.e. in the range of 1020-1040 Kg/m³. The velocity ofsound is about 1430 m/sec in adipose tissue, compared to 1530 m/sec forskin, at normal body temperature. Moreover, on page 85 of the Duckreference, the slope of the sound velocity versus temperature curve forfat is completely different from that of other body fluids. For fat,sound velocity decreases with increasing temperature, dropping to 1400m/sec at 40° C., while that of water and other body fluids rises withtemperature, and is about 1520 m/sec at 40° C. for water and higher forbody fluids and soft tissues other than fat.

A basic model of the electrical properties of cells at the microscopiclevel can be found in Herve Isambert, Phys. Rev. Lett. 80, p 3404(1998). The cell membrane is a poor electrical conductor and thereforebehaves essentially as a local capacitor upon the application of anelectric field across the cell. The charging of the cell membrane underthe application of external electric field generates a stress at thesemembranes, yielding strain which depends on the elastic properties ofthe cell, and which at increased intensity can rupture the cellmembrane, a phenomena known as “electroporation”.

SUMMARY OF THE INVENTION

The present invention provides methods and apparatuses for the treatmentof adipose (fat) tissue. As used herein, the term “treatment of adiposetissue” includes such procedures as fat destruction, inducing fatnecrosis, inducing fat apoptosis, fat redistribution, adipocyte (fatcell) size reduction, and cellulite treatment.

The apparatuses of the invention include at least one ultrasoundtransducer configured to be applied to a skin surface and to radiateultrasound energy through the skin into the subcutaneous adipose tissue.The methods of the invention include directing adipose tissue throughthe skin layer into the subcutaneous adipose tissue.

One embodiment of the invention is based upon a new finding thatpressure gradients of ultrasound energy can lead to selective treatmentof the adipose tissue cells. Without wishing to be bound by a particulartheory, it is believed that the treatment or destruction of adiposetissue cells by pressure gradients generated by ultrasound energy is dueto differences between the mass density of the lipid and that of theother constituents of the adipocytes. As explained below, a pressuregradient in adipose tissue capable of treating or destroying the adiposetissue cells may be generated using a moderately focused ultrasoundtransducer.

In another embodiment of the invention, skin and a region of theunderlying adipose tissue are made to protrude out from the surroundingskin surface. Ultrasound energy is then directed to adipose tissue inthe protrusion. The protrusion may be formed, for example, by applying anegative pressure (vacuum) to the skin region or by mechanicalmanipulation of the skin region. The apparatus of this aspect of theinvention includes an applicator adapted for causing a skin region toprotrude above the surrounding skin region and one or more ultrasoundtransducers which radiate ultrasound energy preferably into theprotrusion.

In yet another embodiment of the invention, ultrasound energy and RFenergy are directed into the adipose tissue. The apparatus of thisaspect of the invention includes an applicator having at least one pairof RF electrodes and at least one ultrasound transducer.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to understand the invention and to see how it may be carriedout in practice, preferred embodiments will now be described, by way ofnon-limiting examples only with reference to the accompanying drawings,in which:

FIG. 1 shows the “view angle” of an ultrasound transducer and vectorsummation of pressure gradients;

FIG. 2 shows an apparatus 4 for reduction of adipose tissue inaccordance with one embodiment of the invention;

FIG. 3 shows an applicator, including an ultrasound transducer for usein the system of FIG. 1;

FIGS. 4 a and 4 b show pressure distribution contours generated by aflat, uniform phase ultrasound transducer;

FIG. 5 shows an applicator configured to radiate ultrasound energy intoa body protrusion created by negative pressure;

FIG. 6 shows the applicator of FIG. 5 provided with degree of freedomfor the ultrasound transducer to rotate and adapt to the protrusion;

FIGS. 7 a and 7 b show an applicator configured to radiate ultrasoundenergy into a body protrusion created by mechanical manipulation of theskin;

FIG. 8 shows an applicator, including at least one ultrasound transducerand at least a pair of RF electrodes;

FIG. 9 shows an applicator including at least one ultrasound transducerand at least a pair of RF electrodes configured to provide RF andultrasound energy into adipose tissue at a protrusion created bymechanical manipulation of the skin;

FIG. 10 shows an applicator including at least one ultrasound transducerand at least a pair of RF electrodes, configured to provide RF andultrasound energy into the adipose tissue at a protrusion created bynegative pressure (vacuum); and

FIG. 11 shows schematically an alternative arrangement of the for RFelectrodes with respect to the ultrasound transducers.

DESCRIPTION OF THE INVENTION

The present invention provides methods and apparatus for treatment ofadipocytes. One aspect of the invention is based upon a new finding thatpressure gradients of ultrasound energy can lead to selective treatmentof the adipose tissue cells. Without wishing to be bound by a particulartheory, it is believed that the selective treatment of adipose tissuecells by pressure gradients generated by ultrasound energy is due todifferences between the mass density of the lipid and that of the otherconstituents of the adipocytes.

When ultrasound energy is directed to a fat cell, for frequencies ofless than about 1 MHz, the wavelength of the ultrasound wave is about1.5 mm, much larger than the fat cell dimensions, which are 50-100 μm.For a plane acoustic wave propagating through the tissue having pressureamplitude P_(max), angular frequency ω and wave vector k=2π/λ, where λis the wavelength, the pressure p(x,t) is:

p(x,t)=P _(max) sin(ωt−kx)   (1)

Neglecting viscosity, the movement of fluids can be calculated fromEuler's equation:

$\begin{matrix}{{\frac{\partial\overset{->}{v}}{\partial t} + {( {\overset{->}{v} \cdot \nabla} )\overset{->}{v}}} = {{- \frac{1}{\rho}}{\nabla p}}} & (2)\end{matrix}$

Where v is the velocity vector, and p is the mass density of the fluid.For small velocities (compared to the sound velocity c) the term (v∇)vcan be neglected and the velocity is proportional to the pressuregradient. For the plane wave of equation 1, since the motion is only inthe x-direction:

$\begin{matrix}{\frac{\partial v}{\partial t} = {{{- \frac{1}{\rho}}\frac{\partial p}{\partial x}} = {\frac{P_{\max}k}{\rho}{\cos ( {{\omega \; t} - {kx}} )}}}} & (3)\end{matrix}$

The velocity is:

$\begin{matrix}{{v( {x,t} )} = {\frac{P_{\max}k}{\rho \; \omega}{\sin ( {{\omega \; t} - {kx}} )}}} & (4)\end{matrix}$

And the local displacement of the fluid is:

$\begin{matrix}{{U( {x,t} )} = {{- \frac{{kP}_{\max}}{\rho \; \omega^{2}}}{\cos ( {{\omega \; t} - {kx}} )}}} & (5)\end{matrix}$

This is the formula for a plane acoustical wave, and for such a waveω=kc and kP_(max) is the pressure gradient.

Let ρ_(1i) be the density of the fluid of the lipid vacuole, and ρ_(cy)the density of the cytoplasm fluid in an adipocyte. The respectiveamplitudes of the displacements can be calculated using equation (5) andsubstituting the corresponding densities:

$\begin{matrix}{{U_{li} = \frac{{kP}_{\max}}{\rho_{li}\omega^{2}}}{U_{cy} = {\frac{{kP}_{\max}}{\rho_{cy}\omega^{2}}(}}} & (6)\end{matrix}$

5

And the relative movement of the two fluids is given by:

$\begin{matrix}{{\Delta \; U} = {{U_{li} - U_{cy}} = {\frac{{kP}_{\max}}{\omega^{2}}( {\frac{1}{\rho_{li}} - \frac{1}{\rho_{cy}}} )}}} & (7)\end{matrix}$

NUMERICAL EXAMPLE

Taking typical values for the adipocytes, ρ_(1i)=916 Kg/m³, ρ_(cy)=1020Kg/m³, and taking P_(max)=4 MPa, ω=2πf, f=250 kHz, and c=1400 m/sec,k=ω/c=1122 m¹, the result is ΔU=0.2 μm. The physical meaning is that thecytoplasm fluid, which is a “minority” fluid in the adipose tissue,oscillates under these conditions with respect to the “majority” fluid,the lipid vacuole, with an amplitude of 0.2 μm. The pressure ofP_(max)=4 MPa corresponds to the power flow density of P²/2Z=6.2MW/m²=620 W/cm² and to a peak pressure gradient of kP_(max)=4.5 GPa/m

A relative displacement of 0.2 μm is significant at the scale ofcellular dimensions. The cytoplasmic layer in the adipocytes has athickness of few micrometers, at some regions of the cell even below 1μm. More specifically, there are regions of the cell where over a lengthof 5-10 μm the width of the cytoplasm changes from below one micrometerto few micrometers. At the narrower regions, the fluid movement of thecytoplasm is damped by viscosity, while at the wider regions thecytoplasm is freer to move. Under the conditions of this example, thereis a difference of displacement of about 0.2 μm over a length of 5-10μm, which means a strain of 0.04-0.02. Since the cell membrane bordersthe cytoplasm, the cell membrane is also subjected to that strain, whichis above the threshold for membrane rupture.

Another effect that may be associated with the above relative movementof adipocyte fluids is selective heating of the cytoplasm. The viscositywill cause some of the kinetic energy to be converted into heat. Sincethe cytoplasm is a minority fluid in the fat tissue and since the lipidvacuole fluid has poor heat conductance, the generated heat willselectively raise the temperature of the cytoplasm and of the cellmembrane bordering it, and may lead to cell necrosis or apoptosis,directly by the local temperature rise at the membrane, or by loweringits strength at the elevated temperature.

For a non-plane wave, kP_(max) in equation 7 must be replaced by themore general pressure gradient, ∇P, in accordance with Euler's equation.It is known to use focusing of the ultrasound energy to generate veryhigh power densities in a focal volume. It helps in two ways: first, itfacilitates production of high power densities by an ultrasoundtransducer, and, second, it generates geometrical selectivity for thedesired effect at the focal volume. However it should be noted thatfocusing, especially strong focusing, enhances the peak pressuresubstantially more than the pressure gradient. As a limiting example, aspherical transducer will generate at its center a very high peakpressure but zero pressure gradient, a manifestation of the fact that atthe center the fluid is not moving. The focusing may be describedphysically as a superposition of plane waves. The pressure amplitude isa scalar, and at the focus the phases of the plane waves are identical,therefore the pressure at the focus is a scalar sum of the pressureamplitudes. However, the pressure gradient, and the displacement whichis proportional to that gradient (by Euler's equation), are vectors,therefore their vector summed amplitude is always smaller than the sumof the magnitudes. More specifically, for strong focusing, theultrasound radiation arrives at the focus from directions with largeangular deviations, reducing the vector sum of the pressure gradient andof the fluid displacement. Therefore, according to the invention, it ispreferred to limit the focusing in order to enhance the pressuregradient at the expense of the pressure amplitude at the focus, so thatthe selective effects on the fat cell will be obtained with undesiredeffects associated with high pressure, such as cavitations.

According to invention, based on the above considerations, an apparatusfor selective destruction of fat cells will include an ultrasoundtransducer, which is moderately focused. Referring to FIG. 1, anultrasound transducer 21 has a focal point 22. The view angle a of thetransducer edges from the focal point correlates with the focusing in avery general way: The larger a the larger the focusing. The displacementand the pressure gradient at the focus generated by waves coming fromthe edges of the transducer, is the vector sum of vector 24 a and vector24 b yielding vector 25. The magnitude of the vector 25 is the magnitudeof the vector 24 a multiplied by 2 cos(α/2) (assuming 24 a is equal to24 b). For α=120° this factor is 1, compared to a factor of 2 for thescalar summation of the pressure at the same point. That is, for large athe pressure is enhanced by the focusing much more then the pressuregradient. Therefore, to obtain the selective fat reduction according tothe invention, the angle a is limited. Preferred values are α<120°, morepreferred α<90°.

According to the invention, based on equation 7, for selectivedestruction of fat cells it is preferred to radiate the ultrasound atlow frequencies, preferably lower than 1 MHz, more preferred below 300kHz. The numerical example above demonstrated that at 250 kHz peakpressure gradient of 4.5 GPa/m is expected to selectively damage fatcells. For moderate focusing this corresponds to a power flow density ofabout 700 W/cm², which is lower than the threshold for cavitation, whichis preferably avoided according to the invention.

Pulsed operation is another way according to the invention for enhancingthe selective effects of the ultrasound for cell destruction. Shortpulses with high intensity generate high strain at the cell membranesdue to the high pressure gradients, while the average power is lowenough to prevent non-selective damage by excessive heating of tissues.Also, for selectively heating of cytoplasm and cell membranes byviscosity it is preferred to apply short intense pulses, since thisviscosity heating effect is non-linear. Typical parameters may be: pulselength between 10 μsec and 10 msec, more preferred between 100 μsec and1 msec. The pulse repetition rate is preferably matched to the pulselength to generate a power duty of 1% to 10%. The average power ispreferably controlled by peak power and duty, in order to control theheating of tissues. While the basic effect is non-thermal, some increasein temperature may be desired, since it reduces the strength of thecells. Preferably tissue heating above normal body temperature is keptbelow 44° C., a temperature known as the pain threshold. Controlledtissue heating according to the invention can be obtained from theultrasound energy, more preferably, RF energy is applied to the treatedvolume as detailed below.

The pulse width and pulse repetition rates are preferably selected to beas far as possible from those optimal for cavitations at the treatedtissues. As disclosed in U.S. Pat. No. 6,113,558, there is an optimalpulse length and pulse repetition frequency for generating cavitations,which are preferably to be avoided. These optimal conditions forcavitations may depend on tissue type and its conditions (such astemperature).

Therefore the specific minimum cavitations conditions may require somematching to the treated site. A cavitations sensor may be included inthe system to assist finding the minimum cavitations conditions.Detection of cavitations can be based on the detection of enhancedreflections at the transmitted ultrasound frequency or by the detectionof ultrasound radiation at half the transmitted frequency, which is aknown indication of cavitations.

The differences in sound velocities between the lipid vacuole and otherfluids in the fat tissue are due to differences in compressibility. Atelevated temperature, the difference increases. (“Physical properties oftissue”, by Francis A. Duck, Academic Press Ltd., 1990, p. 85, FIG.4.1). For example, the sound velocity at 40° C. for fat and other bodyfluids is 1400 m/s and 1520 m/s, respectively. The respective adiabaticcompressibility values are β=5.6×10⁻¹⁰ and β=4.2×10⁻¹⁰. Thus, underthese conditions, the fat is more compressible than other body fluids by30%. However, high pressures are required to exploit this. For example,a pressure of P=10 MPa will generate a relative volume changesΔVN=βP=5.6×10⁻³ and ΔVN=βP=4.2×10⁻³ for the lipid and cytoplasmrespectively. The difference between the fluids is 1.4×10⁻³, which overa scale of typical cell size (50-100 micrometers) will cause a relativemovement of about 0.1 μm. For comparison, the mass density differenceeffect yielded movement of about 0.2 μm at a lower pressure of 4 MPa.

In accordance with one aspect of the invention, at least one ultrasoundtransducer configured to be applied to a skin surface, radiatesultrasound energy through the skin into the subcutaneous fat layers toeffect relative movement between fat cell constituents and to cause fatcell necrosis or apoptosis. According to the invention, a flattransducer having a uniform phase over its surface is used, or amoderately focused transducer with fixed focus, or a phased transducerarray, which can produce a moderate focus and can be electronicallyscanned inside the fat tissue to cover a larger treatment volume.

As explained above, almost all prior art high power ultrasoundapplications use a very high degree of focusing, to enhance the ratiobetween the wanted damage at the target tissue and unwanted damage atthe entrance layers (between transducer and target). However, sinceaccording to the present invention the tuning is for selective damage tofat cells, moderate focusing is used. Moderate focusing can reduceunwanted cavitations effects while not reducing cell rupturing. This isattributed to the fact that cavitations depend on the pressure magnitudeof the ultrasound wave (more specifically, on the negative pressuremagnitude) and not on the pressure gradient.

In another of its aspects, the invention provides a method and apparatusfor delivering ultrasound energy to subcutaneous adipose tissue.According to this aspect of the invention, skin and a region of theunderlying adipose tissue are made to protrude out from the surroundingskin surface. Ultrasound energy is then directed to adipose tissue inthe protrusion. The protrusion may be formed, for example, by applying anegative pressure (vacuum) to the skin region or by mechanicalmanipulation of the skin region. The apparatus of this aspect of theinvention includes an applicator adapted for causing a skin region toprotrude above the surrounding skin region and one or more ultrasoundtransducers which radiates ultrasound energy preferably into saidprotrusion.

Creating a protruding region of skin and underlying adipose tissue andradiating the ultrasound energy preferably parallel or close to parallelto the non-protruding skin surface, has the advantage that the radiationis preferentially directed into the fat tissue inside the protrusionwhile much less ultrasound energy is directed into other body tissues.This reduces the risks of unwanted damage to deep body tissues whichmight be much more sensitive to ultrasound energy, such as lungs, andreduces the pain which is known to be effected when high intensityultrasound radiation heats the bones. A preferred apparatus according tothe invention may include at least two ultrasound transducers withoverlapping irradiated focal volumes inside the adipose tissue. Therelative phases of the emitted radiation from said transducers may becontrolled for maximizing the pressure gradients at selected locationsinside the treated tissue.

In another of its aspects, the present invention provides a method andapparatus for treating subcutaneous adipose tissue. The method comprisesdirecting ultrasound energy and RF energy to the adipose tissue. Theapparatus of this aspect of the invention includes an applicator havingat least one pair of RF electrodes and at least one ultrasoundtransducer. Applicant's co-pending U.S. patent application Ser. No.11/189,129 discloses the combination of high frequency ultrasound energyand RF energy in skin rejuvenation treatments. That applicationdiscloses generating a path of higher RF conductivity by heating ofselected tissue volume by focused ultrasound, and applying RF to thebody which will preferentially flow through the high conductivity path.However the situation with adipose tissue is much more complex, due tothe large differences in the mechanical, electrical and thermalproperties of the majority lipid vacuole fluid and the minoritycytoplasm and intercellular fluids. The total electrical conductivityinside the tissue is composed from direct, Ohmic conductivity of theintercellular fluid, and the Ohmic conductivity of the fluids inside thecells in series with the capacitance of the cell membrane (which is apoor conductor). Since in mature adipose cells, most of the cell volumeis filled with the poorly conducting fluid of the lipid vacuole, most ofthe current flows in the narrow channels of the cytoplasm and theintercellular fluid. Thus, although both RF energy and ultrasound energyare known to be poorly absorbed in fat tissue, most of the absorbedenergy goes to the very thin layers of fluids between the lipidvacuoles, which occupy a very small fraction of the fat tissue volume.While on average, a relatively small amount of energy is absorbed in theadipose tissue, the specific energy transferred to the small volumes ofcytoplasm and intercellular fluid may be high. The fact that the cellmembrane borders these fluids makes the energy investment in thesefluids very effective for destruction of the cell membrane, followed bycell necrosis or apoptosis. Selective heating of these fluids can beachieved by exploiting the difference in the cell fluid properties, asdiscussed above. The RF energy and the ultrasound energy combine inthese specific fluids of the fat tissue, so the desired effects areenhanced without increasing the danger of collateral damage which mightbe produced in other tissues, especially at the skin through which theenergy is delivered, if the energy of a single type is increased toobtain the same effect. The combination of ultrasound energy and RFenergy is more effective in several ways. The heating of tissue byultrasound increases the RF conductivity, so that more energy isdelivered by the RF, and the total heating reduces the cell strength. Inadipose cells, these effects are concentrated mainly in the thin layersof the cytoplasm, so it is more effective for destruction of fat cellsand the selectivity is enhanced by the combination. The combination ofultrasound and RF energy also increases the strain on the fat cellmembrane, since both ultrasound and RF induce such strain on fat cells.The ultrasound wave generates a strain at the fat cell membranes asdiscussed above. The electric fields of the RF also generate strain dueto charging of the membranes (see, for example, Herve Isambert, Supra).Simultaneous application of RF and ultrasound on the same tissue volumeyields a combined strain. In the adipose tissue both effects concentrateat the thin cytoplasm and the adjacent membrane of the adipocytes. Thatcombination may reduce the intensity required from each energy source,so that the risk of collateral damage may be reduced.

In a preferred embodiment of this aspect of the invention, at least oneultrasound transducer and at least two RF electrodes are applied to theprotuberance. A region of skin and underlying adipose tissue to betreated is made to protrude above the surrounding skin surface. The RFenergy may be applied prior to or during formation of the protuberanceto pre-heat the tissue. The RF energy may be applied prior to and/or atleast partially simultaneously with the ultrasound energy. When thisprotrusion is created, the transducers are driven to radiate ultrasoundenergy into the protruding tissues. RF energy is applied to the tissuevia the at least two electrodes, which are either conductive for directinjection of current to the skin, or insulted by a thin layer ofinsulating material for capacitive coupling of energy to the tissue.

Application of RF and ultrasound energies to a protruding region of skinallows treatment of subcutaneous adipose tissue and cellulites.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

FIG. 2 shows an apparatus 4 for applying ultrasound to subcutaneousadipose tissue in accordance with one embodiment of the invention. Anapplicator 3, to be described in detail below, contains one or moreultrasound transducers. The applicator is adapted to be applied to theskin of an individual 5 in a region of skin and underlying adiposetissue to be treated. The applicator 3 is connected to a control unit 1via a harness 2. The control unit 1 includes a power source 8. The powersource 8 is connected to an ultrasound driver 6. The control unit 1contains a processor 9 for monitoring and controlling various functionsof the system. The control unit 1 has an input device, such as a keypad10 that allows an operator to input to the processor 9 selected valuesof parameters of the treatment, such as the frequency, pulse durationand intensity of the ultrasound energy to be directed to the adiposetissue.

The applicator 3 may optionally contain one or more pairs of RFelectrodes in addition to the ultrasound transducers. In this case, thepower supply 8 is connected to an RF generator 15 that is connected tothe RF electrodes in the applicator 3 via wires in the cable 2. When RFelectrodes are included in the applicator 3, the processor 9 may monitorthe electrical impedance between electrodes and determined thetemperature distribution in the vicinity of the target from theimpedance measurements. The system 1 may optionally includes coolingmeans for cooling the skin surface during treatment. For example, thecontrol unit may contain a refrigeration unit 12 that cools a fluid suchas ethanol or water for cooling the applicator 3. The cooled fluid flowsfrom the refrigeration unit 12 to the applicator via a first tube in theharness 2, and flows from the applicator 3 back to the refrigerationunit via a second tube in the harness 2.

The control unit may also include a vacuum pump 18 for evacuating aninterior chamber in the applicator 3, in order to cause a region of theskin surface to protrude above the surround surface. The pump 18 isconnected to an interior chamber of the applicator 3 by a vacuum hose inthe cable 2, as explained below.

In accordance with one aspect of the invention, the applicator 3 isconfigured to deliver ultrasound energy to a region of subcutaneousadipose tissue that so as to generate a pressure gradient in the regionthat ruptures selectively fat cells in the in the region.

FIG. 3 shows an embodiment 3 a of the applicator 3. The applicator 3 aincludes at least one ultrasound transducer 37. The transducer isconnected through a cable, preferably a coaxial cable in the harness 2to the ultrasound driver 6 in the control unit 1. In use, the ultrasoundtransducer is attached to the skin surface 27, preferably withultrasound gel or other ultrasound transmitting material, and generatesa focal volume 33 extending around focal point 22 inside thesubcutaneous adipose tissue 35.

According to one aspect of the invention, the view angle a 23 is limitedto maximize the ratio of pressure gradient to pressure at the focalvolume. Preferred values are a<120°, more preferred a<90°. The controlunit 1 drives the ultrasound transducer at an intensity which producesat the focal volume pressure gradient between 0.5 GPa/m to 50 GPa/m,more preferred between 2 GPa/m to 15 GPa/m. Preferably, the ultrasoundradiation is at a frequency lower than 1 MHz, more preferred below 300kHz. Pulsed operation of the transducer is preferred, preferred pulselengths between 10 μsec and 10 msec, more preferred between 100 μsec and1 msec. The pulse repetition rate is preferably matched to the pulselength to generate a power duty of 1% to 10%.

The ultrasound transducer of the embodiments 3 a may be flat withuniform phase over its radiating surface. This embodiment has theadvantage of simplicity both of the transducer and the drivingelectronics. A flat, uniform phase transducer generates a pressuredistribution, which has a maximum at a focal region, where the pressurecan reach more than 1.5 times that on the transducer surface. FIG. 4shows a specific example for a flat transducer with a 20×20 mm radiatingarea. In the diagrams of FIG. 4, the x-axis is parallel to thetransducer surface while the z-axis is normal to the transducer surface.The origin is at the center of the transducer. Dimensions are in mm.FIG. 4( a) is calculated for ultrasound frequency of 180 kHz, and 4(b)for 250 kHz. The contour numbers are pressures, normalized to a unitpressure on the transducer surface. Since the focusing is very small,contours of pressure gradients at the focal region (not shown) are veryclose to the pressure contours. The choice of the ultrasound frequencycontrols the distance from the transducer face to the maxima, and whichthus determines the depth of treatment. In FIG. 4( a), the region 29 aof maximum pressure has an amplitude of 1.68, and is located betweenz=10 mm to z=20 mm. For a frequency of 250 kHz with the same radiatingarea, the maximum pressure is 1.66 and moves to a region 29 b betweenz=16 mm and z=32 mm, further from the transducer face, as shown in FIG.4( b). It is also preferred to select the thickness of the layer betweenthe radiating surface and the skin so that the skin surface is at aregion of minimum of radiation intensity. Human skin is typically1.5-2.5 mm thick. Referring again to FIG. 4( a), contours of minimumpressure are at a distance of up to about 4 mm from the radiatingsurface. By coating the transducer face with a layer of material havingacoustical impedance close to that of human tissues and having athickness of about 4 mm, a ratio of about 1.66 between the maximumpressure in the subcutaneous adipose tissue and maximum pressure at theskin is obtained.

A curved transducer and/or transducer with a lens which producesstronger fixed focusing can be applied according to the invention.Another embodiment will have the transducer 37 made as a phased array,with a multi-channel phased driver in the control unit 1. An example ofa phased array ultrasound system, with a detailed description of highintensity phased array technology as known in the art, can be found inthe paper by K. Y. Saleh and N. B. Smith, Int. J. Hyperthermia Vol. 20,NO. 1 (February 2004), pp. 7-31. An apparatus based on a phased array ismore complicated both in the transducer and in the driving electronics.However it has the following advantages:

a. Control of degree of focusing.

b. Control of depth and position of focal volume.

c. Possible scanning of focal volume inside a selected volume of tissue.

At least one element of the array, or any additional small transducer inthe non-array embodiments, may be a sensor comprising a receiver that istuned to half the transmitting frequency to detect generation ofcavitations in the body tissue, and/or tuned to the transmittedfrequency to detect enhanced reflectivity from hard body tissue or fromcavitations. According to the output of this sensor, the control unit 1varies the radiated ultrasound properties (pulse length, repetition rateand intensity) to minimize their unwanted effects. A phased arrayembodiment also enables positioning the focal volume away from the hardtissue and/or reducing the focusing to reduce cavitations.

The embodiment 3 a of the applicator has the advantage of simplicity,however, since focusing is limited, there is a risk that residualultrasound energy will enter deeper into the body and hit sensitivetissue such as lungs and effect unwanted damage. Also, if this residualultrasound energy were to hit bones, it might cause pain. To reducethese risks, the embodiments 3 b to 3 g may be used. These embodimentsexploit the very high flexibility of fat tissue, and based on generatinga protrusion out of the body surface and attaching at least oneultrasound transducer to that protrusion. This transducer radiatespreferably in a direction parallel to the undisturbed body surface, orat least as close as possible to that optimal angle. Under theseconditions, the adipose tissue inside the protrusion is exposedpreferentially, while much less radiation arrives at deeper body tissue.These embodiments can be based on mechanical manipulations and/or onapplication of negative pressure (vacuum) as detailed below.

FIG. 5 shows the embodiment 3 b of the applicator 3. The applicator 3 bis shown in cross-section in FIG. 5 and includes a hollow dome 40 havingan interior chamber 41. At least one ultrasound transducer 42 a andpossibly more transducers, such as 42 b, are located in the interiorchamber 41. The dome 40 is applied to the skin and a negative pressureis generated in the interior chamber 41 by pumping the air out throughport 44 by the vacuum pump 18 located in the control unit 1 that isconnected to the interior chamber by a vacuum hose 46 in the harness 2.Due to the negative pressure, body tissue 45 including skin andsubcutaneous tissue 35, is sucked into volume 41, thus protruding abovethe surrounding skin surface. This suction applies the skin surface ontothe ultrasound transducers 42 a and 42 b. The transducers are connectedthrough cables 48 a and 48 b in the harness 2 to the ultrasound driver 6in the control unit 1. The cables may include coaxial cables for drivingthe transducers and optionally for sending output signals from sensorslocated in the applicator 3 b, such as temperature sensors or ultrasoundsensors, to the processor 9 in the control unit 1 for processing by theprocessor 9.

The ultrasound transducers 42 a and 42 b have focal volumes 47 a and 47b located preferably in the protruding portion of the adipose tissuelayer 35. The ultrasound transducer may be of any type described abovefor embodiment 3 a. A flat, uniform phase transducer, having theradiation pattern as detailed in FIG. 4, is applied with properselection of dimensions and frequency to obtain maximum intensity insidethe adipose tissue at the protrusion. Any fixed focus transducer canalso be applied with the focal volume preferably at that region.According to a preferred embodiment, the transducer 42 a (and also 42 bif included) will be a phased array as described for applicator 3 a. Thephased array will either focus the radiation at the optimal region ofthe protrusion, or scan the adipose tissue inside the protrusion.Although phased array is more complicated, it has the advantages ofoptimal delivery of energy into the adipose tissue at the protrusionwith minimal residual energy going to other tissues. In a preferredembodiment, at least two transducers 42 a, 42 b are used so that theirvolumes of maximum intensity 47 a and 47 b overlap. Preferably thephases of the transducers are controlled, and matched in a way thatmaximizes the ultrasound intensity in the overlapping volumes or tomaximize the pressure gradients there. The transducer 42 a (and thetransducer 42 b and as well as any other transducers when present) ispreferably oriented in the interior chamber 41 so that the direction ofultrasound radiation from the transducer is close to being parallel tothe skin surface outside the protrusion. In this orientation,penetration of the ultrasound energy to internal tissues and organsbelow the subcutaneous adipose layer is reduced or eliminated. Anotherembodiment will create this preferred direction of radiation by buildinga transducer which radiates at an angle to its surface. That angle canbe fixed and produced by inserting a material with appropriate soundvelocity in front of the transducer, or by a variable radiation anglefrom a phased array, controlled by unit 1.

A pressure sensor may be included inside the interior chamber 41. Inthis case, the control unit 1 may be configured to drive the ultrasoundtransducers 42 a and 42 b when the measured pressure is within apredetermined range. The propagation of ultrasound radiation from thetransducer into the tissue can be monitored by measuring the electricalimpedance of the transducer, that is, by measuring the AC voltage andcurrent on the transducer. Variations in power transmission from thetransducer are manifested by changes in the voltage-current relation onthe transducer.

The radiating area of each of the transducers 42 a and 42 b may be, forexample, between 5×5 mm to 50×50 mm, more preferably between 10×20 mm to20×40 mm, depending on the volume of tissue to be treated.

FIG. 6 shows an embodiment 3 c of the applicator 3 in which thetransducers 42 a and 42 b are allowed a degree of freedom so that theycan acquire an orientation that conforms to the skin surface in theprotrusion. In the embodiment of FIG. 6, at least one ultrasoundtransducer, or the two ultrasound transducers 42 a and 42 b are mountedon hinges 52 a and 52 b respectively, and displaced towards the centerby respective springs 55 a and 55 b. The electrical cables 48 a and, 48b are flexible, so that the transducers are free to rotate about thehinges 52 a and 52 b. Negative pressure is created inside the interiorchamber 41 as explained above with reference to FIG. 5. As the tissue issucked into the interior chamber 41, it pushes the transducers 42 a and42 b against the force of springs 55 a and 55 b, thus causing them torotate on the hinges 52 a and 52 b against the force of the springs 55 aand 55 b. The direction of maximum acoustical radiation (beam direction)of the transducer 42 a is indicated in FIG. 6 by ray 58, creating anangle β with the normal 57 to the non-protruding skin surface. Asexplained above with reference to FIG. 5, the angle β is preferably asclose as possible to 90° (i.e. the radiation is close to being parallelto the non-protruding skin surface). In embodiment 3 c, the angle βdepends on the properties of the tissues at the treatment site and onthe controllable parameters, such as the negative pressure amplitude,its application time and the spring constants of the springs 55 a and 55b. The closer the angle β is to 90°, the lower the amount of energy thattraverses the adipose tissue 35 and enters other tissues deeper insidethe body.

The ultrasound transducer(s) of embodiment 3 c can be any of thoseapplicable to embodiment 3 a and 3 b. When a phased array is used, thephase of each element is controlled by an electronic driving circuit inthe control unit 1, so that the focal volume can be aimed easily by theelectronic control of the array at a desired region inside the adiposetissue. When the transducers 42 a and 42 b in the embodiment 3 c of theapplicator 3 are phased arrays, an angle encoder can be associated witheach of the hinges 52 a and 52 b to determine the orientation of thetransducers 42 a and 42 b. The desired focal point can then bedetermined according to their orientation, and the control unit 1 willphase the array to bring the focal volume to that position inside thefat tissue. The time scale of vacuum pumping is between 50 msec and 1sec, which is also the time scale of variation of the angles of thetransducers, while the focal point can be shifted within a few tens ofmicroseconds to the desired location. Another important advantage of aphased array is the ability to scan a selected volume within the adiposetissue, by electronically controlling the phase of the array elements.The electronic scanning is fast, and can cover a large volume within thetypical pumping time. Also, the degree of focusing can be controlled bythe electronics.

In another embodiment, the generation of the protrusion of skin andunderlying adipose tissue is done by mechanical manipulation of the skinsurface. This embodiment avoids the need to vacuum system as is requiredwhen the protrusion is formed by negative pressure.

FIG. 7 shows an example of an embodiment 3 d of the applicator 3 whichdelivers a mechanical manipulation of a skin surface in order togenerate a protruding region of skin tissue and underlying adiposetissue. The applicator 3 d includes a base element 300, which may beconnected to a handle (not shown). Grooves 301 and 302 are providedinside the base element 300 in which bars 303 and 304, respectively, canmove laterally. Rods 305 are 306 are attached to the bars 303 and 304,respectively. Plates 307 and 308 are connected to the lower end of therods 305 are 306, respectively. The lower surface of these plates ispreferably rough or covered with a suitable high-friction material 309in order to enhance friction and reduce slippage over the skin.Ultrasound transducers 311 and 312 are attached to plates 307 and 308respectively through hinges 313 and 314 respectively so as to be free torotate about the hinges. The springs 315 and 316 displace thetransducers, 311 and 312, respectively towards the skin surface 27. Atthe upper end of the rods 305 and 306, rods 317 and 318, respectively,are connected. The rods 317 and 318 are driven by an actuator 319.

The embodiment 3 d has two ultrasound transducers, arrangedsymmetrically. This is by way of example only and a non-symmetricalmechanical manipulator with only one transducer or more than twotransducers may be used as required in any application.

The embodiment 3 d of the applicator 3 is used to create a protrusion ofa skin surface as follows. The plates 309 and 310 are applied onto theskin surface 27 at a site to be treated, as shown in FIG. 7 a. Theactuator 319 pulls the rods 305 and 306 inwards together with the plates307 and 308 and the transducers 311 and 312. As shown in FIG. 7 b, dueto the high coefficient of friction between the layer 309 and the skinsurface, the body tissue 320 is pushed upwards so as to form aprotrusion 330. The springs 313 and 314 are designed so that the momentthey exert on the transducers 311 and 312 is low enough to allow thetransducers to rotate about the hinges 313 and 314, respectively, so asto allow formation of the protrusion, while at the same time, ensuringgood coupling of ultrasound energy from the transducers 311 and 312 tothe skin surface 27. After the protrusion has been formed, thetransducers 311 and 312 radiate ultrasound energy into the body tissue,to effect reduction of the fat in focal volumes 47 a and 47 b in thesubcutaneous adipose tissue 35. The ultrasound transducers may becontained inside the plates 307 and 308. In this case, it is desirableto allow a degree of freedom of movement to these plates, so as to allowthem to conform to the protrusion as it forms, either freely, or byforcing them to rotate simultaneously with the lateral motion.

The plates 307 and 306 and/or the transducers 311 and 312 may be curvedin any desired shape in order to obtain a protrusion having a desiredshape. The transducers 311 and 312 of the embodiment 3 d may be any ofthose applicable for the other embodiments, 3 a-3 c, that is, planartransducers, fixed focus transducers or phased array transducers. If aphased array is used, in a similar way to embodiment 3 c (FIG. 6), aposition encoder is preferably added to hinges 313 and 314, and thefocal position electronically matched to the orientation of thetransducers.

The apparatus 4, with the applicator 3 b or 3 c or 3 d, may beconfigured to deliver ultrasound energy to a region of subcutaneousadipose tissue so as to generate a pressure gradient in the region thatruptures cells in the in the region. Since this effect is obtained usingmoderate focusing of the ultrasound radiation in a volume ofsubcutaneous adipose tissue to be treated, when the overlying skinsurface is made to protrude above the surrounding surface, a largerpower may be applied with lower risk to internal organs and tissues.

Ultrasound energy may be delivered to the skin together with RF energy;as explained above. FIG. 8 shows schematically an embodiment 3 e of theapplicator 3 in which an ultrasound transducer 71 is located between twoRF electrodes 72 and 73. The transducer and RF electrodes are supportedby an insulating housing 77. Application of the applicator 3 e to theskin surface 27, applies both the ultrasound transducer 71 and the RFelectrodes 72 and 73 to the skin surface 27, to obtain good coupling ofthe RF and ultrasound energies to the skin surface. An electricallyconductive ultrasound conductive gel may be applied to the skin prior tothe treatment. The ultrasound transducer is driven through cable 74 inthe harness 2, while cables 75 and 76 supply the RF voltage to theelectrodes from the RF generator 15 in the control unit 1.

FIG. 9 shows an embodiment 3 f of the applicator 3 in which RFelectrodes have been incorporated into the embodiment 3 d of FIG. 7. Forexample, in FIG. 9, RF electrodes 341 and 342 are located adjacent tothe transducers 311 and 312. The RF electrodes are driven through cables75 and 76, which are included in harness 2 (not shown). The RFelectrodes can be incorporated into the plates 307 and 308 or on thetransducers 311 and 312. In the later embodiment, a thin film ofelectrically conducting material having negligible ultrasoundattenuation is preferably applied to each transducer face touching theskin 27, and connected to the RF power supply 15 in control unit 1.

FIG. 10 shows another embodiment 3 g of the applicator 3 in which a pairof RF electrodes 81 and 82 has been added to the embodiment 3 b of FIG.5. The RF electrodes 81 and 82 are located at the sides of the dome 40,so they can contact the skin. The RF electrodes 81 and 82 are driven bythe RF driver 15 in the control unit 1 by cables 83 and 84 in theharness 2. The electrodes 81 and 82 and the cables 83 and 84 areelectrically insulated from the housing and from the ultrasoundtransducers. The housing 40 is preferably made of insulating material.The high conductivity contour through the skin layer 85 is longer andtakes less energy than in the planar embodiment 3 e shown FIG. 8, so ahigher electric field 86 is created in the deep adipose tissue. Theelectric field heats the minority fluids in the adipose tissue andgenerates strain on the adipose tissue cell membranes, as explainedabove. Preferably the applicators 3 f and 3 g are designed to make theregions of maximum electric field and maximum ultrasound intensity atleast partially overlaps within the adipose tissue, to maximize thecombined effects of the RF and the ultrasound energies. A pair of RFelectrodes can similarly be added to applicator 3 c.

The applicator 3 g has RF electrodes parallel to the ultrasoundtransducers. It is also possible according to the invention to locatethe RF electrodes at other positions, which provide at least partialoverlap of the RF electric field and the ultrasound radiation within theadipose tissue. FIG. 11 shows schematically another possible arrangementof the RF electrodes and the ultrasound transducers in side view (FIG.11 a), and in top view (FIG. 11 b). For simplicity, FIG. 11 shows onlyone pair of RF electrodes 91 and 92, and a pair of ultrasoundtransducers 93 and 94.

Preferred RF parameters, for all the embodiments, are: RF frequencybetween 100 kHz and 50 MHz, more preferred between 500 kHz and 5 MHz.Applied RF voltages are between 10V peak to 1000V peak, more preferredbetween 30V peak to 300V peak for a distance of 10 mm betweenelectrodes, and higher voltage for greater electrode spacing. The RFelectrode spacing may be between 5 mm to 50 mm and their length may bebetween 5 mm to 50 mm. Preferably, the ultrasound transducer covers mostof the area between the electrodes. The ultrasound transducer may beflat with uniform phase where the depth of treatment is controlled bythe frequency, or a fixed focus transducer or a phased array transducerwith the capability of scanning the focal volume, as in embodiments 3a-3 d. Preferably, the RF energy is applied in pulses, typically between10 μsec 500 msec, more preferred between 1 msec to 100 msec. Preferablythe RF and ultrasound pulses overlap at least partially.

Monitoring the contact between the RF electrodes and the body may bedone by measuring the voltage across the electrodes and the current, andcalculating from that the impedance between the electrodes. Based onexperience with a certain electrode structure, a range of impedances canbe defined that are sufficient for the application of the RF power. Asin the previous embodiments, coupling of the ultrasound energy to thebody can be monitored by measuring the transducer impedance.

The applicator embodiments 3 b-3 g are independent of any specificphysical model for the destruction of fat cells. However, it isadvantageous in all embodiments to apply the ultrasound energy in a waythat maximizes the selective destruction of fat cells, as was done withembodiment 3 a, namely, to exploit the unique structure of fat cells toeffect relative movement between the adipose cell constituents, leadingto strain and selective heating at the cell boundary, following bydamage to the cell membrane which cause cell necrosis or apoptosis.

Any of the above embodiments may be adapted for delivering infra-red(IR) energy to the skin surface. Delivering of IR illumination to theskin enhances the aesthetic treatment, so that fat, cellulites and skincan be treated simultaneously. The IR illumination can be applied toskin regions not covered by the ultrasound transducer or the RFelectrodes.

1.-163. (canceled)
 164. An applicator for selective treatment of adiposetissue, the applicator comprising: (a) a hollow dome having an interiorchamber communicating through a port with a vacuum pump, the hollow domeconfigured to be applied to skin and suck into the interior chamber theskin and subcutaneous tissue, forming a protrusion protruding above thesurrounding skin surface; (b) one or more moderately focused ultrasoundtransducers located in the interior chamber of the dome and having theirfocal volumes located in the protruding portion of the adipose tissuelayer; and (c) a pair of RF electrodes located at the sides of thehollow dome and electrically isolated from the dome and the ultrasoundtransducers, the electrodes driven by an RF driver operative to provideRF to the electrodes such that when the electrodes are in contact withthe skin the RF creates a high electric field in the adipose tissue.165. The applicator according to claim 164, wherein the skin andsubcutaneous tissue, sucked into the interior chamber are applied ontothe ultrasound transducers.
 166. The applicator according to claim 164,wherein regions of maximum electric field and ultrasound focal volumesat least partially overlap within the adipose tissue, to maximize thecombined effects of the RF and the ultrasound energies.
 167. Theapplicator according to claim 164, wherein the ultrasound transducersemit ultrasound that heats the tissue (in the focal volumes) andincreases the RF conductivity such that more energy is delivered by theRF into the heated (focal volumes) tissue yielding a combined stress andreducing adipose tissue cell strength.
 168. The applicator according toclaim 164, wherein the electric field created in the adipose tissueheats minority fluids in the adipose tissue and generates additionalstrain on the adipose tissue cell membranes.
 169. The applicatoraccording to claim 164, wherein the moderately focused ultrasoundtransducers are one of a group of transducers consisting of flattransducers, curved transducers or transducers with a lens.
 170. Theapplicator according to claim 169, wherein the moderately focusedultrasound transducers are phased array transducers and wherein phasesof the transducers are controlled, and matched in a way that maximizesthe ultrasound intensity in the focal volumes and the pressure gradientsin the focal volumes.
 171. The applicator according to claim 164,wherein in order to avoid penetration of ultrasound energy to internaltissues and organs below the adipose tissue, the moderately focusedultrasound transducers in the interior chamber are oriented so that thedirection of ultrasound radiation from the transducers is close to beingparallel to surface of the skin outside the protrusion.
 172. Theapplicator according to claim 164, wherein for selective treatment ofadipose tissue the transducer provides moderately focused ultrasoundenergy confined to a view angle of less than 120 degrees.
 173. Theapplicator according to claim 164, wherein for selective treatment ofadipose tissue the transducer provides moderately focused ultrasoundenergy confined to a view angle of less than 90 degrees.
 174. Theapplicator according to claim 164, wherein the moderately focusedultrasound transducers generate a pressure gradient between 2 GPa/m to15 GPa/m and the moderately focused ultrasound energy has a frequencylower than 1 MHz.
 175. The applicator according to claim 164, whereinpropagation of ultrasound radiation from the moderately focusedultrasound transducer into the tissue is monitored by measuring theelectrical impedance of the transducer and wherein variations in powertransmission from the transducer are manifested by changes in thevoltage-current relation on the transducer.
 176. The applicatoraccording to claim 164, further comprising a sensor comprising areceiver tuned to half the moderately focused ultrasound transmittingfrequency the receiver configured to detect and control appearance ofcavitation in the treated tissue and control pressure level such that itdoes not cause cavitation in lipid, cytoplasm and intercellular fluids.177. The applicator according to claim 164, wherein at least onetransducer of moderately focused ultrasound energy applied to the tissuein the protrusion generates a pressure gradient in the adipose tissue;the pressure gradient generates a relative movement between the fat cellconstituents having different densities.
 178. The applicator accordingto claim 164, wherein the RF electrodes, are one of a group ofelectrodes consisting of conductive electrodes for direct injection ofcurrent to the skin, and electrodes insulated by a thin layer ofinsulating material for capacitive coupling of energy to the tissue.179. The applicator according to claim 164, wherein the RF electrodes,are a thin film of electrically conducting material having negligibleultrasound attenuation applied to each transducer face touching theskin.
 180. The applicator according to claim 164, wherein monitoring thecontact between the RF electrodes and the skin is done by measuringvoltage across the electrodes and the current, and calculating from thatvoltage and current the impedance between the electrodes and monitoringof the coupling of the ultrasound transducers to the skin is done bymeasuring the transducer impedance.
 181. The applicator according toclaim 167, wherein the temperature of selectively heated cells is below44 degrees Celsius.